Amino acid mixture for use in treatment of uremic conditions

ABSTRACT

A mixture intended for nitrogen nutrition is disclosed which contains as a source of nitrogen a mixture of essential amino acids optionally combined with certain semi-essential amino acids. The mixture may be administered in either tablet or solution form to the patient and causes a lowering in blood urea nitrogen in combination with a positive nitrogen accumulation.

United States Patent [191 Bergstriim et al.

[ Oct. 9, 1973 [73] Assignee: Aktiebolag Astra, Sodertalje,

Sweden [22] Filed: Nov. 3, 1970 [217] Appl. No.: 86,625

Related US. Application Data [63] Continuation-impart of Ser. No.820,638, April 30,

1969, abandoned.

[30] Foreign Application Priority Data Nov. 7, 1969 Sweden 15280/69 [52]US. Cl. 424/319 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/319[56] References Cited UNITED STATES PATENTS 3,080,234 3/1963 .larowski424/319 Primary Examiner-Sam Rosen Att0rney-Brumbaugh, Graves, Donohue &Raymond 57 ABSTRACT A mixture intended for nitrogen nutrition isdisclosed which contains as a source of nitrogen a mixture of essentialamino acids optionally combined with certain semi-essential amino acids.The mixture may be administered in either tablet or solution form to thepatient and causes a lowering in blood urea nitrogen in combination witha positive nitrogen accumulation.

34 Claims, No Drawings AMINO ACID MIXTURE FOR USE IN TREATMENT OF UREMICCONDITIONS The present application is a continuation-in-part of ourearlier copending U.S. application, Ser. No. 820,638, filed Apr. 30,1969, now abandoned.

The present invention relates to a therapeutic mixture containing aminoacids possibly in combination with one or both of the semi-essentialamino acids L- arginine and L-histidine, which may be administered to apatient in either tablet or solution form. The invention also relates toa process for the preparation of such tablets and solutions and a methodfor the treatment of uremic conditions which are caused by renalinsufficiency.

In one embodiment the present invention relates to infusion solutionsintended for intravenous nitrogen nutrition in which the source ofnitrogen comprises essential amino acids optionally combined with one orboth of the semiessential amino acids L-arginine and L-histidine. Theinvention also includes a process for the preparation of such solutionsand a method for the treatment of uremic conditions caused by renalinsufficiency by administering the solutions.

Attempts have been made to give nitrogen nutrition to uremic patients bymeans of a special diet. These attempts are documented in the followingreferences: W. C. Rose, 8 Fed.Prc. 546 (1949); C. Giordano, 62 J. Lab.Clin. Med. 231 (1963); C. Giordano et al., 45 J Clin. Invest. 1013(1966) and N6. DeSanto et al., Biachim. Appl. 556 (1968). According tosuch proposals essential amino acids were administered to the uremicpatient as the only nitrogen source in addition to the diet nitrogen.During this treatment the patients were given amino acid nitrogen inrather small doses for the reason that considerable difficulties wereinvolved with peroral administration of the essential amino acidsbecause their bad taste could not be masked in an acceptable manner byincorporation into tablets coated with chocolate or similar flavorfulsubstances. When coatings were used, a large number of tablets wererequired to be administered since the material of the coating in such acase was the dominant component in the tablet. Quite frequently peroraladministration caused nausea and vomiting. These difficulties oftencaused interruption of the treatment. Patients participating in thetests often were given egg proteins corresponding essentially to thesame nitrogen quantity. Although a certain reduction of the blood ureanitrogen (BUN) was obtained, only a slight positive nitrogen balance wasobserved. It did not exceed the value of 1 gram of nitrogen accumulationper day. The result and the effect of this previous treatment method wasso unsatisfactory that in several cases the patients had to be treatedat the same time by dialysis.

According to one embodiment of the present invention it is possible toadminister nitrogen intravenously to patients suffering from renalinsufficiency or a very reduced kidney function. At the same time aconsiderable lowering of the blood urea nitrogen content is obtained incombination with a very pronounced nitrogen accumulation. This nitrogenaccumulation may attain about 6 grams or more per day. One of the mostimportant advantages of the amino acid solutions according to theinvention is that such a lowering of the blood urea nitrogen incombination with a positive nitrogen accumulation often makes itpossible to eliminate or postpone the dialysis treatment of the patientwhich was inevitable according to previous methods of treatment. Theseeffects must be considered as unexpected and are to be regarded as avery important medical development.

A further advantage obtained by the use of the amino acid solutionaccording to the invention is that a pronounced improvement in thegeneral condition of the patients with a lowering of the concentrationof accumulated protein decomposition products is obtained. A furtherunexpected advantage obtained by the use of the solutions according tothe invention is that the improvement in the general condition of thepatient continues even after the interruption of the treatment. This isa very important advantage which is not achieved by means of previouslyknown means and methods of treatment.

The amino acid solutions according to the present invention containpreferably from about 2.5 to about 15.0 grams per liter of nitrogenoriginating from essential and semi-essential amino acids. The solutionscontain a mixture of essential amino acids in approximately thefollowing molar proportions: v

0.0l30-0.0850 moles of L-phenyl alanine 0.0l65-0.l050 moles of L-leucine00145-00900 moles of L-methionine 0.0025-0.0200 moles of L-tryptophan0.0l05-0.0700 moles of L-isoleucine 0.01 10-0.0700 moles of L-lysine0.0080-00550 moles of L-threonine 0.0135-0.0850 moles of L-valine perliter. In addition thereto it is also possible to incorporate00125-00800 moles of L-arginine 00070-00450 moles of L-histidine perliter.

According to a particularly preferred embodiment the solutions contain:

00375-00675 moles of L -phenyl alanine 00500-00850 moles of L-leucine0.0425-0.0750 moles of L-methionine 0.0075-0.0l25 moles of L-tryptophan0.0300-00550 moles of L-isoleucine 00325-00575 moles of L-lysine0.0225-0.0425 moles of L-threonine 00400-00700 moles of L-valine perliter. These solutions may also be given a content of 00375-00650 molesof L-arginine 0.0200-0.0375 moles of L-histidine per liter. PreferablyL-histidine is the only semiessential amino acid added. The basic aminoacid L- histidine is preferably dissolved in the form of an acetate toprevent the development of acidosis which can occur if the chloride formis used.

The pH of the solutions is adjusted to fall within the range of 4.9 to7.0 by addition of a pharmaceutically acceptable acid. Acids which aredecomposed by the body to water and carbonic acid, i.e. organic acidscontaining only carbon, oxygen and hydrogen, e.g. acetic acid, lacticacid and the like, are preferred. The pH range may be extended up to7.0, and preferably the pH is adjusted to 6.0-7.0 to be more compatiblewith physiological pH. The preferred acid for the adjustment of the pHis acetic acid. Hydrochloric acid normally should not be used since itmay be dangerous in acidotic cases. Acetic acid, on the other hand, hasno influence on the acid-base balance in the body.

' The preparations according to the invention are primarily intended forthe treatment of those uremic conditions which are related to kidneydamage or a reduced kidney function but may, of course, be used in otherconditions where nitrogen nutrition is appropriate, e.g., in catabolicconditions. To obtain the best results patients should be placed on alow nitrogen (low protein) diet prior to and during treatment. Theprotein content of the diet should not exceed about 3.0 g per day, andthe daily calorie intake should be between 2,000 and 3,000 calories.

The invention is illustrated by the following Examples:

EXAMPLE 1 A mixture of L-arginine, L-phenyl alanine, L- histidine,L-isoleucine, L-leucine, L-lysine, L- methionine, L-threonine,L-tryptophan and L-valine-in quantities corresponding to a final contentof 0.0375 moles of L-arginine, 0.0400 moles of L-phenyl alanine, 0.0215moles of L-histidine, 0.0320 moles of I..- isoleucine, 0.0505 moles ofL-leucine, 0.0330 moles of L-lysine, 0.0445 moles of L-methionine,0.0255 moles of L-threonine, 0.0075 moles of L-tryptophan and 0.0415moles of L-valine per liter was dissolved with stirring in 50 liters ofsterile water, whereafter sterile water was added up to about 90 liters.The pH value was adjusted to 6.0 by addition of acetic acid. The volumeof the solution was then adjusted to 100 liters by addition of sterilewater and sterile filtered nitrogen was bubbled through the solution inorder to make it free from oxygen. The solution thus obtained wasfiltered and placed in infusion bottles under nitrogen atmospherewhereafter the bottles were sterilized by heating in an autoclave at120C for about minutes.

EXAMPLE 2 A mixture of L-arginine, L-phenyl alanine, L- histidine,L-isoleucine, L-leucine, L-lysine, L- methionine, L-threonine,L-tryptophan and L-valine in quantities corresponding to a final contentof 0.0630 moles of L-arginine, 0.0665 moles of L-phenyl alanine, 0.0355moles of L-histidine, 0.0535 moles of L- isoleucine, 0.0840 moles ofL-leucine, 0.0550 moles of L-lysine, 0.0740 moles of L-methionine,0.0420 moles of L-threonine, 0.0110 moles of L-tryptophan and 0.0685moles of L-valine per liter was dissolved with stirring in 50 liters ofsterile water, whereafter sterile water was added up to about 90 litersand then the pH value of the solution was adjusted to 6.0-6.5 byaddition of concentrated acetic acid. The volume of the solution wasthen adjusted to 100 liters by addition of sterile water and finallysterile filtered nitrogen was bubbled through the solution in order tomake it free from oxygen. The solution thus obtained was filtered andfilled into infusion bottles under nitrogen atmosphere whereafter thebottles were sterilized by heating in an autoclave at 120C for minutes.

EXAMPLE 3 Example 2 was repeated but L-arginine was omitted from thesolution. in this way a solution containing L- histidine as the onlysemi-essential amino acid was obtained.

EXAMPLE 4 A mixture of 5.25 grams of L-isoleucine, 8.25 grams ofL-leucine, 6.00 grains of L-1ysine acetate (equivalent to L-lysine),8.25 grams of L-methionine, 8.25 grams of L-phenyl alanine, 3.75 gramsof L-threonine, 1.88 grams of L-tryptophan, 6.00 grams of L-valine, and4.12 grams of L-histidine were dissolved in one liter of sterile water.The pH was adjusted to 6.7 by addition of acetic acid. A 400 ml aliquotcontained 2.6 grams of amino acid nitrogen and 18 milliequivalents ofacetate. Persons of normal or robust stature may receive a dosage of 400ml per 24 hours whereas persons of small stature may receive 200 ml per24 hours. The total infusion time should not be less than 4 and 3 hours,respectively. Larger doses of 600800 ml in 5-6 hours for a 4-5 dayperiod may be used if necessary. Stabilization of the blood ureanitrogen content to as low a level as possible often requires dailyinfusions for a 2- to 3- week period. 0

EXAMPLE 5 The patient was a 48-year old man with terminal 1 chronicrenal failure due to interstitial nephritis (abuse ofphenacetin-containing anodynes). He had been treated twice withperitoneal dialysis. On admission his plasma urea nitrogen was 110 mgper ml and the plasma creatinine 1 1.2 mg per 100 ml. Endogenouscreatinine clearance was repeatedly found to be less than 3 ml perminute. He was initially given a diet containing 2.7 g of nitrogen perday. A regimen with a very low nitrogen content (less than 0.3 g perday) was then instituted. This regimen was based on concentratedflavore'd carbohydrate solutions (e.g. Hycal) and proteinfree bread andbutter, altogether corresponding to 2000 i100 kcal and 0.1-0.3 g ofnitrogen per day.

After 6 days on this diet (of which the last 4 days constituted periodI) intravenous administration of the following solution of essentialamino acids was started:

CONCENTRATION Amino acid g/liter gNitrogen/liter L-isoleucine 5.25 0.56L-leucine 8.25 0.88 L-lysine acetate 6.00 1.16 L-mcthionine 8.25 0.75L-phenyl alanine 8.25 0.70 L-threonine 3.75 0.44 L-tryptophan 1.88 0.25L-valine 6.00 0.7 1

An alternative addition was L-histidine neutralized by acetic acid) witha concentration in the solution of about 4.12 g/liter and 1.12 gN/liter.

Four hundred ml of the solution, corresponding to 2.2 g of nitrogen weregiven daily which represented 3 times the minimum requirement. Duringthe first 4-day period of amino acid administration (Period 11 in Table1 given below) 1.65 g of L-histidine (dissolved as acetate),corresponding to 0.45 g of nitrogen, was added to the infused aminoacids. During consecutive 4- or 6-day periods (Ill VI) the essentialamino acids were given alternatively with and without addition ofhistidine. Period VI was followed by 1 day without any infusion (PeriodVII) and during the subsequent period (VIII), L-histidine was replacedby an isonitrogenous amount of L-p'roline. This was followed by a finalperiod, (1X), when L-histidine was again added to the essential aminoacids. After the study the patient was referred to training for homedialysis.

The total body water was determined twice during the study usingtritium-labelled water and liquid scintillation counting. The nitrogenbalance was corrected -in muscular strength, disappearance of fatigueand anorexia and a decrease of paresthesia in the legs.

With the patients diet containing 2.7 g of nitrogen the plasma ureanitrogen rapidly decreased to 71 mg per 100 ml.

The intial period of protein-free diet (I) brought about a further rapiddecrease in plasma urea nitrogen. The decrease in urea nitrogencontinued during the following 4-day period (II), when essential aminoacids and L-histidine were infused daily. The nitrogen balance was notdetermined during this period. Subsequently, the balance was found to bepositive over the whole study, except for 1 day (VII) when no aminoacids were given. However, the balance was more positive during theperiods when histidine was added to the solution, as compared withperiods without histidine lowing quantitativeresults were obtained:

when only essential amino acids without histidine were infused. Sincethese days followed immediately after a period when histidine wasincluded, this elevation was probably due to an overlap of the histidineeffect. In order to exclude overlap effects from one period to the nextand also to obtain periods of comparable length, the nitrogen balancefor the periods V, VI and VII was calculated not only for the entireperiod (a) but also for the three or four last days of the period (b),omitting the days when overlapping may have occurred.

The influence of L-histidine on the balance became more significant whenthe nitrogen balance was corrected for changes in the total urea pool.The difference in nitrogen balance between periods with and withoutL-histidine was greater than could be accounted for by the extranitrogen supplied as histidine. Addition of L-proline to the essentialamino acids failed to give as strong a positive balance as the additionof histidine. Plasma urea decreased during each period when L-histidinewas added, whereas it tended to rise in the L-histidine-free periods.

Plasma creatinine concentration remained at the same high levelthroughout the study. Body weight and total body water volume remainedconstant. The fol- TABLE I Mean total Primary N-intake mean N CorrectedPlasma urea N Day No. of Amino acids inf. +food balance N balance (g/100ml) Period number days infused (g/day) (g/day) (g/day) (start-end) l l-44 0 0.06 3.80 1.33 71-45 11 5-8 4 EAA+ H 2.86 -30 111 9-12 4 EAA 2.450.47 0.88 30-26 1V 13-16 4 EAA+H 2.90 +1.17 +1.47 26-23 Va 17-22 6 EAA2.38 0.66 0.25 23-29 Vb 19-22 4 EAA 2.37 0.48 0.07 25-29 Vla 23-28 6EAA+ H 2.91 +1.04 +1.38 29-24 Vlb 25-28 4 EAA H 2.91 +1.05 +1.46 28-24VII 22 l 0 0.10 1.37 1.78 24-25 V1l1a 30-33 4 EAA+ P 2.85 +0.69 +0.5925-26 V111b 30-33 3 EAA+ P 2.85 +0.62 +0.76 27-26 1X 34-36 3 EAA+ H 2.85+1.08 +1.76 26-21 Mean daily nitrogen balance of the patient duringintravenous amino acid administration. Corrected nitrogen balance meansthat the primary balance is corrected for changes of body ureacalculated from changes of plasma urea nitrogenconcentrationrnultiplieclbybody v1 a tel volume.

EAA essential amino acids, L-histiditiEIP administration.

In all three periods when histidine was given and the nitrogen balancedetermined (IV, VI, IX), the effect on the balance was already apparenton the first day of administration. On the other hand, the balance wasstill z ssstats s s t d w fir t 4315.9?33119 )5.

EXAMPLE 6 Patients were given a diet containing about 2.2g of nitrogenper day and-2.400 kcal/day and were also infused with an intravenoussolution of essential amino acids (in acetate form). No L-histidine orL-arginine were included. The daily dose was 2.2 g. The following 592Ets ltta a TABLE 11 Plasma P.U-N creatinine Nitrogen balance Endogen (mg/ml) (mg/100 ml) (g N/day) creatinine Body Total clearance weight bodyNon- Cor- Case Sex Age Diagnosis (ml/min) (kg) water 1 Days Before AfterBefore After corrected rected l M 51 P.C.K. 5 75 45 3 148 136 16 16 3.31.5 2 F 36 P.C.K. 5 61 32 6 75 55 10 10 2.3 1.1 3 F 56 CF. 5 74 31 4 103-l8 l8 l.8 l.5 4 F 49 P.C.K. 5 51 28 5 71 68 12 13 -1.4 1.2 5 F 54P.C.K. 6 58 34 4 100 88 13 12 3.5 2.5 5 58 34 4 79 51 11 11 1.5 +0.9 6 F37 C.P. 5 45 25 4 156 114 l2 10 4.3 l.7 5 45 25 1 100 99 12 12 23 2.1 7F 67 OF. 5 56 31 3 133 115 12 11 14 +0.4

Table 11 Continued 8 M 47 C.G. 67 4O 3 92 75 ll ll 3.6 1.2

H) F 50 C.P. 7 59 32 9 75 34 8 7 -O.9 +0.5

II F 47 C.G. 5 49 27 12 114 69 12 13 2.0 -0.9

12 F 32 C.G. 5 56 31 4 111 95 12 12 V 3.1 -1.8

13 F 22 C.G. 5 54 I 30 Not studied Not studied Not studied Not studied14 F 23 CG. 5 52 '29 Not studied Not studied Not studied stu ie M 37A.N. 5 54 I 33 Not studied Not studied Not studied No;

studie 16 F 50 P.C.K. 7 5 56 30 Not studied Not studied Not studied :10;

stu 1e Clinical data. Proteinpoor diet (2.7 g N/day). P.C.K.=Polycystickidney disease. C.P.=Chronic pyelonephritis. C.G.=Chronicglomerulonephritis. A.N.= Analgetic nephritis. x= Determined bytritiated water. *P.U-N= Plasma urea nitrogen.

EXAMPLE 7 in an improved lowering effect on BUN, but still the ni-Patients were infused with a solution of the essential trogen balanceswere not satisfactory- It was amino acids of Example 6 supplemented with(145 g shown that if histidine was given together with the esr dose fbhistidine sential amino acids an improvement in nitrogen bal- Table I"gives the results. ance could be demonstrated in most cases and a goodTABLE 111 Plasma creatinine Nitrogen balance P.UN* (mg/100 ml) (mg/100ml) (8 N/day) Body Total weight body A.A. Non- Case (kg) water 1 Days gN/day Before After Before After corrected Corrected Protein-poor diet(2.7 g N/day) supplied with essential l-amino acids (2.19 g N) infuseddaily. A.A.= l-amino acids. P.UN*= Plasma urea nitrogen. x= Determinedby tritiated water.

EXAMPLE 8 effect maintained on the BUN. For these reasons fur-Thirty-three severe uremic patients were treated with f", Studies h beenF out w con- 8 low protein diet (27 g of nitrogen/day) and varioustaming the eight essential amino aclds and histidine. At kinds of aminoacid solutions including patients with Present a total of uremc patientshave been treated BUN up to 150 mg percent and Serum creatinine levels m20 treatment periods and of these 16 have been conup to 15 mg percentand with creatinine clearance rates siderec. successful In the few Punder treatment of less than 7 ml/min. A total number of 54 periods ofwho did not respond to therapy, It was obvlous treatment were performedand 4] of these were classi that lack of response was associated wlthmtercurrent 9 l I I fied as successful. A successful treatment periodrefers dlsease or iz f the diet to a stationary or declining BUN and anamelioration 150K396 (N )Smdles. l that following Heinof the nitrogenbalance. In most treatment periods the l mm low-Prowl and mtrallenouslyi nitrogen balance was followed and a positive nitrogen mere? amineaclds a protein synthesls.takes place.m balance usually obtained afterintravenous amino acid uremlc pauems the basis of these Isotope stildlesinfusion. Nitrogen balances which were initially at a regular treatmentwith Solution I has been establrshed negative level of 3-5 g of nitrogenper 24 hours in many 0 an g g g g a Up 22 cases became positive at alevel of 2-5 g of nitrogen per slons o o u ave een given 0 ureml pa- 24hours. A summary of the results of treatments can 2 :5 zi ggzggg gig gand long-term and ssnin @6595 B l w m r Results Successful Unsuccessfulv Infusion Treatment treatment treatment Amino acid solutions (400 mlN-content) Patients given periods period period 1. essential amino acids2.19 g N and histidine 0.44 g N (chloridefree) 15 286 20 16 4 11. it)essential amino acids 2.19 g N and arginine 1.15 g N and histidine 0.44g N 22 332 32 25 7 b) essential amino acids 2.19 g N and histidine 0.44g N In the initial studies the eight essential amino acids Kind ofatients ll'l uSiOnS with together with the semi-essential amino acidsarginine I and histidine were given to a number of uremic pahemodialysis14 377 tients. In a subsequent series of treatments only theperitonealdial sis 30 446 eight essential amino acids were given whichresulted Total y 44 823 9 EXAMPLE 9 A 47-year old man with chronicglomerulonephritis and uremia, BUN about 110 mg percent, creatinineclearance about 7 ml/min. was given a low-protein diet for 4 days.Continuing the diet he was treated on day 5 with daily intravenousinfusions of a solution of essential amino acids with L-histidine andL-arginine. His BUN decreased and the nitrogen balance became positive.On days 14 and 15 he was given the solution by stomach tube. The BUNrose and decreased only when intravenous infusions were resumed. TableIV summarizes the general results obtained:

TABLE IV BUN N-balance Serum creatimne Day rug/100 ml 5 N/day g/l ml 198 -2 13.0 12.0 7 +1 1 12.0 9 62 +2.0 11.0 m 8 l.6 12 58 11.5 14 56 13.5+1.8 10.0 16 80 10.0 17 78 +1.6 19 64 9.8

EXAMPLE 10 A woman, 23 years old, was treated for 18 days by intravenoustransfusion. She had severe uremia and a creatinine clearance of about 5ml/min. Table V summarizes the general results obtained:

TABLE V BUN N-balance Plasma creatinine Day mg/lOO ml g N/day mg/IOO ml1 l 15 +2.0 10.0 2 100 na 10.2 3 108 +0.8 9.8 4 102 +1.8 10.6 5 98 +0.89.8 6 86 +1.8 9.4 7 84 +2.0 9.0 8 84 +2.4 9.0 9 80 +2.0 9.6 10 76 +2.29.0 l 1 na 2.4 8.8 12 68 +2.0 8.6 13 64 +2.4 8.8 14 62 +2.2 8.6 15 62+2.4 8.4 16 60 +3.0 8.8 17 58 +2.8 9.8 18 na na 9.6 19 60 na 9.6

EXAMPLE 1 l A 23-year old woman had chronic glomerulonephritis and acreatinine clearance of about 3 ml/min. Daily infusions of a solution ofessential amino acids plus histidine and arginine (3.7 g of nitrogen perday) were given for 7 days followed by the same quantities of essentialamino acids only (2.19 g of nitrogen per day for 8 days). The BUNstabilized itself at a level of about 50 mg percent and the nitrogenbalance remained slightly positive. Nitrogen loss with the feces was notdeducted. When only L-histidine was added to the solution of essentialamino acids the balance improved without any increase of the blood urealevel. Table VI summarizes the general results obtained:

10 TABLE VI BUN N-balance Plasma creatinine Day mg/l00 ml g N/day mg/100ml 1 98 na 13.5 2 76 +2.! 12.5 3 76 +2.3 12.5 4 70 +2.2 14.5 5 62 +3.814.4 6 60 +3.4 12.2 7 56 +3.0 11.6 8 58 +1.5 12.8 9 60 +1.6 11.8 10 55+1.5 12.2 11 54 +1.4 11.2 12 54 +2.2 11.8 13 52 +1.6 11.2 14 55 +1.912.0 15 60 +1.8 12.2 16 58 +0.7 12.0 17 58 +2.4 10.6 18 50 +2.8 10.8 1949 +2.5 11.2 20 48 +1.7 11.0 21 50 +2.4 11.8 22 52 +2.4 10.6 23 na na11.8 24 na na 12.4

According to another embodiment of the present invention it is alsopossible to administer nitrogen perorally to patients suffering fromrenal insufficiency or a very reduced kidney function. It has now beenfound that the intervals between the treatment with intravenous nitrogenaddition solutions can be considerably prolonged by oral administrationof nitrogen nutrition to the patients by using chloride-free tabletsformed from the disclosed mixture of essential amino acids during theperiod of time immediately following the time for the intravenousnitrogen addition. By this technique a better utilization of thetreatment resources in the hospital is achieved, and the treatment ofthe uremic conditions from the patients point of view is considerablysimplified since the intervals are prolonged between the hospitaltreatments. These effects must be considered as unexpected and are to beregarded as an important medical innovation with regard to the shortageof hospital beds and the great need of treatment actually required.

The tablets which are prepared according to the invention suitablycontain a mixture of essential amino acids in the following internalmolar proportions:

0.0l30-0.0850 moles of L-phenyl alanine 0.0l0.l050 moles of L-leucine0.0145-0.0900 moles of L-methionine 00025-00200 moles of L-tryptophan0.0l05-0.0700 moles of L-isoleucine 0.01 l00.0700 moles of L-lysineacetate 0.0080-00550 moles of L-threonine 00135-00850 moles of L-valine.

A preferred range is:

00375-00675 moles of L-phenyl alanine 00500-00850 moles of L-leucine0.0425-0.075O moles of L-methionine 0.00750.0l25 moles of L-tryptophan00300-00550 moles of L-isoleucine 0.03250.0575 moles of L-lysine acetate0.02250.0425 moles of L-threonine 0.04000.0700 moles of L-valine.

Furthermore, it is also possible to incorporate in the tablet thesemi-essential amino acids L-arginine and L- histidine in the followinginternal molar proportions:

00125 00800 moles of L-arginine 0.00700.0450 moles of L-histidine.

A preferred range for these components is:

00375-00650 moles of L-arginine 00200-00375 moles of L-histidine.

The additon of L-histidine is particularly advantageous for achievementof a good treatment result and may be considered as an essential aminoacid to uremic patients. If necessary, basic amino acids are present inthe acetate formsince the chlorides may cause acidosis to develop.

According to a particularly preferred embodiment, tablets are preparedcomprising:

0.110 g L-leucine 0.025 g L-tryptophan 0.1 10 g L-methionine 0.110 gL-phenyl alanine 0.070 g L-isoleucine 0.113 g L-lysine acetate 0.050 gL-threonine 0.080 g L-valine 0.055 g L-histidine per tablet unit. Atypical tablet unit will weigh from about 0.73 g to 0.81 g.

The mixture may be a film-coated tablet, may be placed in capsule formor may be in any other suitable dosage form. One daily dose of nitrogengenerally corresponds to about 30 tablets with the above-givencomposition.

The invention is illustrated by the following working examplesillustrating the preparation of the tablet. The examples set forth thevarious components in weight units which fall within the disclosed rangeof molar proportions:

EXAMPLE l2 (Composition of 10,000 tablets) L-isoleucine 700 g L-leucine1,100 g L-lysine acetate (corresponds to 800 g L-lysine) 1,130 gL-methionine 1,100 g L-phenyl alanine 1,100 g L-threonine 500 gL-tryptophan 250 g L-valine 800 g All the above substances are groundthrough a 1 mm sieve and are mixed together. The powder mixture ismoistened with a binder solution of 150 g polyvinylpyrrolidone in 1,200g of 50 percent ethanol, and the solvent is removed by drying in a fancupboard at 50C. The dried mash is ground through a 2 mm sieve, is

mixed with starch and 80 g of magnesium stearate and EXAMPLE l3(Composition for 10,000 tablets) L-isoleucine 700 g Lleucine 1,100 gL-lysine acetate (corresponds to 800 g L-lysine 1,130 g L-methionine1,100 g L-phenyl alanine 1,100 g L-threonine 500 g L-tryptophan 250 gL-valine 800 g L-histidine 550 g All substances are ground through a 1mm sieve and are mixed together. The powdered mixture is moistened witha binder solution of 150 g polyvinyl pyrrolidone in 1,200 g of 50percent ethanol, and the solvent is removed by drying in a fan cupboardat 50C. The dried mash is ground through a 2 mm sieve, is mixed withstarch and g of magnesium stearate and is compressed into tablets with aweight of about 0.76 g in an excenteror rotating tabletting machine. Thedisintegrating time of the tablets is determined according to theprocess described in the British Pharmacopaeia. In order to mask theunpalatable taste of the tablets they are coated with a thin film ofpolyvinyl acetate and polyethylene glycol by a spray process asdescribed above.

EXAMPLE 14 (Preparation of 10,000 tablets) In the first step a mixtureof:

L-leucine 1,100 g L-lysine acetate (corresponding to 800 g L-lysine)1,130 g lactose 500 g L-isoleucine 700 g ,L-methionine 1,100 g L-phenylalanine 1,100 g L-threonine 500 g L-tryptophan 250 g L-valine 800 g istreated as mentioned above. The quantity of polyvinyl pyrrolidone addedis 75 to 150 g dissolved in 800 g to 1,000 g ethanol vol percent).

In a third step the two granules prepared in the two preceding steps aremixed together with 70-100 g magnesium stearate as a lubricant, and thefinal mixture is compressed in a single punch machine and a rotarymachine into tablets with a weight of 0.73-0.76 g.

The tablets are spray-coated with a solution comprising:

Parts by Weight polyvinyl acetate 1.5 3.0 polyethylene glycol ethanol(95 vol An airless spray gun may be used to apply the coating solution.The 10,000 tablets can be sprayed with 1,400 g to 1,800 g of thesolution.

EXAMPLE 15 (Preparation of 10,000 tablets) L-histidine 550 g L-leucine1,100 g L-lysine acetate (corresponding to 800 g L-lysine 1,130 glactose coated with a solution of certified color, 3 percent.

We claim:

1. A mixture useful in providing nutrition for patients suffering fromuremic conditions comprising essential amino acids in the followinginternal molar proportions:

0.0130-00850 moles of L-phenyl alanine 00165-01050 moles of L-leucine00145-00900 moles of L-methionine 00025-00200 moles of L-tryptophan00105-00700 moles of Lisoleucine 0.01 -00700 moles of L-lysine0.0080-00550 moles of L-threonine 0.0135-00850 moles of L-valine.

2. A mixture as claimed in claim 1 which further comprises L-histidinein the proportion of about 0.0070-00450 moles.

3. A mixture as claimed in claim 2 which further comprises L-arginine inthe proportion of about 00125-00800 moles.

4. A mixture as claimed in claim 1 which comprises amino acids in thefollowing proportions:

00375-00675 moles of L-phenyl alanine 00500-00850 moles of L-leucine00425-00750 moles of L-methionine 00075-00125 moles of L-tryptophan0.0300-00550 moles of L-isoleucine 00325-00575 moles of L-lysine00225-00425 moles of L-threonine 00400-00700 moles of L-valine.

5. A mixture as claimed in claim 4 which further comprises 00200-00375moles of L-histidine.

6. A mixture as claimed in claim 5 which further comprises 00375-00650moles of L-arginine.

7. An infusion solution intended for intravenous nutrition comprising:

00130-00850 moles of L-phenyl alanine 00165-01050 moles of L-leucine00145-00900 moles of L-methionine 00025-00200 moles of L-tryptophan00105-00700 moles of L-isoleucine 00110-00700 moles of L-lysine00080-00550 moles of L-threonine 00135-00850 moles of L-valine per literof solution in water, the pH of which solution being adjusted to fallwithin the interval 6.0 to 7.0 by

addition of a pharmaceutically acceptable organic acid containing onlycarbon, oxygen and hydrogen.

8. An infusion solution according to claim 7, wherein the solution alsocontains 00125-00800 moles of L- arginine and 00070-00450 moles ofL-histidine per liter.

9. An infusion solution according to claim 7, wherein the solution alsocontains 0.0070-00450 moles of l..- histidine per liter.

10. An infusion solution according to claim 7, comprising:

0.0375-00675 moles of L-phenyl alanine 00500-00850 moles of L-leucine0.0425-00759 moles of L-methionine 00075-00125 moles of L-tryptophan00300-00550 moles of L-isoleucine 0.0325-00575 moles of L-lysine0.0225-00425 moles of L-threonine 0.0400-00700 moles of L-valine perliter of solution.

11. An infusion solution according to claim 10, wherein the solutionalso contains 00375-00650 moles of L-arginine and 00200-00375 moles ofL- histidine per liter.

12. An infusion solution according to claim 10, wherein the solutionalso contains 00200-00375 moles of L-histidine per liter.

13. An infusion solution according to claim 7, wherein the pH of thesolution is adjusted to fall within the interval 6.0 to 7.0 by additionof a pharmaceutically acceptable organic acid.

14. An infusion solution according to claim 7, wherein the pH of thesolution is adjusted to fall within the interval 60 to 7.0 by additionof acetic acid.

15. Method for the treatment of uremic conditions caused by renalinsufficiency comprising administering by intravenous infusion to apatient a solution of:

0.0130-00850 moles of L-phenyl alanine 00165-01050 moles of L-leucine0.0145-00900 moles of L-met-hionine 00025-00200 moles of L-tryptophan0.0105-00700 moles of L-isoleucine 0.01 10-00700 moles of L-lysine0.0080-00550 moles of L-threonine 00135-00850 moles of L-valine perliter of solution in water, the pH of which solution being adjusted tofall within the interval 6.0 to 7.0 by addition of a pharmaceuticallyacceptable organic acid containing only carbon, oxygen and hydrogen.

16. Method according to claim 15, wherein the solution also contains00125-00800 moles of L-arginine and 00070-00450 moles of L-histidine perliter.

17. Method according to claim 15, wherein the solution also contains00070-00450 moles of L-histidine per liter.

18. Method according to claim 15, wherein the solution comprises:

00375-00675 moles of L-phenyl alanine 00500-00850 moles of L-leucine00425-00750 moles of L-methionine 00075-00125 moles of L-tryptophan00300-00550 moles of L-isoleucine 00325-00575 moles of L-lysine00225-00425 moles of L-threonine 00400-00700 moles of L-valine per literof solution.

19. Method according to claim 18, wherein the solution also contains0.0375-00650 moles of L-arginine and 0.0200-00375 moles of L-histidineper liter.

20. Method according to claim 18, wherein the solution also contains00200-00375 moles of L-histidine per liter.

21. Method according to claim 15, wherein the pH of the solution isadjusted to fall within the interval 6.0 to 7.0 by addition of apharmaceutically acceptable organic acid, containing only carbon, oxygenand hydrogen.

22. Method according to claim 15, wherein the pH of I the solution isadjusted to fall within the interval 6.0 to 7.0 by addition of aceticacid.

24. A method as claimed in claim 23, in which the tablet furthercomprises a protective film.

25. A method as claimed in claim 24, in which the. film comprises acompound selected from the group consisting of polyvinyl acetate andpolyethylene glycol.

26. A method as claimed in claim 23, in which the tablet comprisesessential amino acids in the following internal molar proportions:

0.0375-00675 moles of L-phenyl alanine 0.0500-00850 moles of L-leucine00425-00750 moles of L-methionine 00075-00125 moles of L-tryptophan00300-00550 moles of L-isoleucine 00325-00575 moles of L-lysine00225-00425 moles of L-threonine 00400-00700 moles of L-valine.

27. A method as claimed in claim 26, in which the tablet furthercomprises a protective film.

28. A method as claimed in claim 27, in which the protective filmcomprises a compound selected from the group consisting of polyvinylacetate and polyethylene glycol.

QL. W.

29. A tablet comprising essential amino acids in the following internalmolar proportions:

00130-00850 moles of L-phenyl alanine 00165-01050 moles of L-leucine00145-00900 moles of L-methionine 00025-00200 moles of L-tryptophan00105-00700 moles of L-isoleucine 0.01 10-00700 moles of L-lysine00800-00550 moles of L-threonine 00135-00850 moles of L-valine.

30. A tablet as claimed in claim 29 which further comprises a protectivefilm.

31. A tablet as claimed in claim 30, in which the protective filmcomprises a compound selected from the group consisting of polyvinylacetate and polyethylene glycol.

32. A tablet as claimed in claim 29, comprising amino acids in thefollowing internal molar proportions:

00375-00675 moles of L-phenyl alanine 00500-00850 moles of L-leucine00425-00750 moles of L-methionine 00075-00125 moles of L-tryptophan0.0325-00575 moles of L-lysine 00225-00425 moles of L-threonine00400-00700 moles of L-valine.

33. A tablet as claimed in claim 32, which further comprises aprotective film.

34. A tablet as claimed in claim 32, in which the protective filmcomprises a compound selected from the group consisting of polyvinylacetate and polyethylene

2. A mixture as claimed in claim 1 which further comprises L-histidinein the proportion of about 0.0070-0.0450 moles.
 3. A mixture as claimedin claim 2 which further comprises L-arginine in the proportion of about0.0125-0.0800 moles.
 4. A mixture as claimed in claim 1 which comprisesamino acids in the following proportions: 0.0375-0.0675 moles ofL-phenyl alanine 0.0500-0.0850 moles of L-leucine 0.0425-0.0750 moles ofL-methionine 0.0075-0.0125 moles of L-tryptophan 0.0300-0.0550 moles ofL-isoleucine 0.0325-0.0575 moles of L-lysine 0.0225-0.0425 moles ofL-threonine 0.0400-0.0700 moles of L-valine.
 5. A mixture as claimed inclaim 4 which further comprises 0.0200-0.0375 moles of L-histidine.
 6. Amixture as claimed in claim 5 which further comprises 0.0375-0.0650moles of L-arginine.
 7. An infusion solution intended for intravenousnutrition comprising: 0.0130-0.0850 moles of L-phenyl alanine0.0165-0.1050 moles of L-leucine 0.0145-0.0900 moles of L-methionine0.0025-0.0200 moles of L-tryptophan 0.0105-0.0700 moles of L-isoleucine0.0110-0.0700 moles of L-lysine 0.0080-0.0550 moles of L-threonine0.0135-0.0850 moles of L-valine per liter of solution in water, the pHof which solution being adjusted to fall within the interval 6.0 to 7.0by addition of a pharmaceutically acceptable organic acid containingonly carbon, oxygen and hydrogen.
 8. An infusion solution according toclaim 7, wherein the solution also contains 0.0125-0.0800 moles ofL-arginine and 0.0070-0.0450 moles of L-histidine per liter.
 9. Aninfusion solution according to claim 7, wherein the solution alsocontains 0.0070-0.0450 moles of L-histidine per liter.
 10. An infusionsolution according to claim 7, comprising: 0.0375-0.0675 moles ofL-phenyl alanine 0.0500-0.0850 moles of L-leucine 0.0425-0.0759 moles ofL-methionine 0.0075-0.0125 moles of L-tryptophan 0.0300-0.0550 moles ofL-isoleucine 0.0325-0.0575 moles of L-lysine 0.0225-0.0425 moles ofL-threonine 0.0400-0.0700 moles of L-valine per liter of solution. 11.An infusion solution according to claim 10, wherein the solution alsocontains 0.0375-0.0650 moles of L-arginine and 0.0200-0.0375 moles ofL-histidine per liter.
 12. An infusion solution according to claim 10,wherein the solution also contains 0.0200-0.0375 moles of L-histidineper liter.
 13. An infusion solution according to claim 7, wherein the pHof the solution is adjusted to fall within the interval 6.0 to 7.0 byaddition of a pharmaceutically acceptable organic acid.
 14. An infusionsolution according to claim 7, wherein the pH of the solution isadjusted to fall within the interval 6.0 to 7.0 by addition of aceticacid.
 15. Method for the treatment of uremic conditions caused by renalinsufficiency comprising administering by intravenous infusion to apatient a solution of: 0.0130-0.0850 moles of L-phenyl alanine0.0165-0.1050 moles of L-leucine 0.0145-0.0900 moles of L-methionine0.0025-0.0200 moles of L-tryptophan 0.0105-0.0700 moles of L-isoleucine0.0110-0.0700 moles of L-lysine 0.0080-0.0550 moles of L-threonine0.0135-0.0850 moles of L-valine per liter of solution in water, the pHof which solution being adjusted to fall within the interval 6.0 to 7.0by addition of a pharmaceutically acceptable organic acid containingonly carbon, oxygen and hydrogen.
 16. Method according to claim 15,wherein the solution also contains 0.0125-0.0800 moles of L-arginine and0.0070-0.0450 moles of L-histidine per liter.
 17. Method according toclaim 15, wherein the solution also contains 0.0070-0.0450 moles ofL-histidine per liter.
 18. Method according to claim 15, wherein thesolution comprises: 0.0375-0.0675 moles of L-phenyl alanine0.0500-0.0850 moles of L-leucine 0.0425-0.0750 moles of L-methionine0.0075-0.0125 moles of L-tryptophan 0.0300-0.0550 moles of L-isoleucine0.0325-0.0575 moles of L-lysine 0.0225-0.0425 moles of L-threonine0.0400-0.0700 moles of L-valine per liter of solution.
 19. Methodaccording to claim 18, wherein the solution also contains 0.0375-0.0650moles of L-arginine and 0.0200-0.0375 moles of L-histidine per liter.20. Method according to claim 18, wherein the solution also contains0.0200-0.0375 moles of L-histidine per liter.
 21. Method according toclaim 15, wherein the pH of the solution is adjusted to fall within theinterval 6.0 to 7.0 by addition of a pharmaceutically acceptable organicacid, containing only carbon, oxygen and hydrogen.
 22. Method accordingto claim 15, wherein the pH of the solution is adjusted to fall withinthe interval 6.0 to 7.0 by addition of acetic acid.
 23. A method oftreating uremic conditions in a patient comprising administering to thepatient a tablet comprising essential amino acids in the followinginternal molar proportions: 0.0130-0.0850 moles of L-phenyl alanine0.0165-0.1050 moles of L-leucine 0.0145-0.0900 moles of L-methionine0.0025-0.0200 moles of L-tryptophan 0.0105-0.0700 moles of L-isoleucine0.0110-0.0700 moles of L-lysine 0.0080-0.0550 moles of L-threonine0.0135-0.0850 moles of L-valine.
 24. A method as claimed in claim 23, inwhich the tablet further comprises a protective film.
 25. A method asclaimed in claim 24, in which the film comprises a compound selectedfrom the group consisting of polyvinyl acetate and polyethylene glycol.26. A method as claimed in claim 23, in which the tablet comprisesessential amino acids in the following internal molar proportions:0.0375-0.0675 moles of L-phenyl alanine 0.0500-0.0850 moles of L-leucine0.0425-0.0750 moles of L-methionine 0.0075-0.0125 moles of L-tryptophan0.0300-0.0550 moles of L-isoleucine 0.0325-0.0575 moles of L-lysine0.0225-0.0425 moles of L-threonine 0.0400-0.0700 moles of L-valine. 27.A method as claimed in claim 26, in which the tablet further comprises aprotective film.
 28. A method as claimed in claim 27, in which theprotective film comprises a compound selected from the group consistingof polyvinyl acetate and polyethylene glycol.
 29. A tablet comprisingessential amino acids in the following internal molar proportions:0.0130-0.0850 moles of L-phenyl alanine 0.0165-0.1050 moles of L-leucine0.0145-0.0900 moles of L-methionine 0.0025-0.0200 moles of L-tryptophan0.0105-0.0700 moles of L-isoleucine 0.0110-0.0700 moles of L-lysine0.0800-0.0550 moles of L-threonine 0.0135-0.0850 moles of L-valine. 30.A tablet as claimed in claim 29 which further comprises a protectivefilm.
 31. A tablet as claimed in claim 30, in which the protective filmcomprises a compound selected from the group consisting of polyvinylacetate and polyethylene glycol.
 32. A tablet as claimed in claim 29,comprising amino acids in the following internal molar proportions:0.0375-0.0675 moles of L-phenyl alanine 0.0500-0.0850 moles of L-leucine0.0425-0.0750 moles of L-methionine 0.0075-0.0125 moles of L-tryptophan0.0325-0.0575 moles of L-lysine 0.0225-0.0425 moles of L-threonine0.0400-0.0700 moles of L-valine.
 33. A tablet as claimed in claim 32,which further comprises a protective film.
 34. A tablet as claimed inclaim 32, in which the protective film comprises a compound selectedfrom the group consisting of polyvinyl acetate and polyethylene glycol.